VERGFR-1 in the Uterine Circulation During Pregnancy

描述(由申请人提供)：在怀孕期间，子宫血流量显著增加，这是一个复杂而完整的血管扩张和反应性改变的过程。血管内皮生长因子(VEGFR)和胎盘生长因子(PlGF)均为多效性生长因子，其血管作用由VEGFR-1和VEGFR-2两种主要受体亚型介导。PlGF是由胎盘产生和分泌的，与血管内皮生长因子不同，它与VEGFR-1受体特异性结合。鉴于最近的发现表明PlGF-VEGFR-1能够刺激血管扩大和血管扩张，并调节VEGFR-2受体上的VEGFR-2的作用，PlGF-VEGFR-1的故事令人兴奋。VEGFR-1信号的抑制与先兆子痫、胎儿和胎盘重量减轻以及子宫循环动脉重塑受损有关。拟议的研究试图通过解决四个具体目标来了解妊娠如何影响VEGFR-1激活的信号和功能下游作用：目标1将定义改变的VEGFR-1信号对子宫血流和血管重构的影响。目的研究该受体在子宫动脉和静脉中的定位及其与妊娠和血管大小的关系，并确定切应力和雌激素对其表达的影响。目的3阐明VEGFR-1激活产生动脉和静脉血管扩张的机制，重点是钾通道参与膜超极化，以及血管扩张剂分子的分子同一性。目的4将确定VEGFR-1激活增强子宫静脉通透性的细胞途径(顺向和跨细胞)和信号机制。四种大鼠体内病毒过表达模型(sVEGFR-1、sVEGFR-2、PlGF、VEGF)和外科子宫角结扎模型将用于这些研究，并结合体外评估动脉和静脉的结构变化，以及受体调节和信号转导的潜在机制。子宫血管的生长、血管扩张和通透性增加都有助于增加妊娠期的子宫血流量。该项目将对生理信号通路产生新的见解，该信号通路的异常与先兆子痫、子宫血管重构不足以及有利于过度血管收缩的血管活性信号的失衡有关。公共卫生相关性：这个项目是关于VEGFR-1的生物学作用的调查，VEGFR-1是一种血管内皮生长因子/PlGF生长因子家族的受体，在妊娠期间的子宫循环中。这些研究对女性的健康具有潜在的重要意义，因为VEGFR-1的失调最近与先兆子痫有关。令人惊讶的是，人们对它对子宫血管的作用知之甚少，这个项目将确定它在怀孕期间调节子宫血管变化的机制。

DESCRIPTION (provided by applicant): During pregnancy, a profound increase in uterine blood flow occurs via a complex and integrated process of vascular enlargement and altered reactivity. VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) are pleiotropic growth factors whose vascular actions are mediated by two dominant receptor subtypes: VEGFR-1 and VEGFR-2. PlGF is produced and secreted by the placenta and, unlike VEGF, binds specifically to the VEGFR-1 receptor. The PlGF-VEGFR-1 story is exciting in view of recent findings that reveal its ability to stimulate vessel enlargement and vasodilation, and to modulate the actions of VEGF on the VEGFR-2 receptor. Inhibition of VEGFR-1 signaling is associated with preeclampsia, reduced fetal and placental weights and compromised arterial remodeling of the uterine circulation. The proposed studies seek to understand how gestation affects the signaling and functional downstream actions of VEGFR-1 activation by addressing four Specific Aims: Aim 1 will define the effects of altered VEGFR-1 signaling on uterine blood flow and vascular remodeling. Aim 2 will characterize the localization and molecular biology of this receptor in uterine arteries and veins as a function of gestation and vessel size, and determine how shear stress and estrogen affect its expression. Aim 3 will elucidate the mechanisms by which VEGFR-1 activation produces arterial and venous vasodilation, with a focus on potassium channel involvement in membrane hyperpolarization, and on the molecular identity of the vasodilator molecules. Aim 4 will determine the cellular pathway (para- vs. trans-cellular) and signaling mechanism by which VEGFR-1 activation amplifies uterine venous permeability. Four rat in vivo viral overexpression models (sVEGFR-1, sVEGFR-2, PlGF, VEGF) and a surgical uterine horn ligation model, in which implantation is restricted to one side of the uterus, will be used for these studies and combined with in vitro assessment of structural changes in arteries and veins, and of mechanisms underlying receptor regulation and signaling. The growth, vasodilation and increased permeability of uterine vessels all contribute to increasing uterine blood flow during gestation. This project will generate new insights into a physiological signaling pathway whose aberrance has been implicated in preeclampsia, insufficient uterine vascular remodeling, and an imbalance of vasoactive signals favoring excessive vasoconstriction. PUBLIC HEALTH RELEVANCE: This project is an investigation of the biological actions of VEGFR-1, a receptor for the VEGF/PlGF growth factor family, in the uterine circulation during pregnancy. These studies are potentially important to women's health because dysregulation of VEGFR-1 has recently been associated with preeclampsia. Surprisingly little is known about its actions on the blood vessels of the uterus, and this project will determine the mechanisms by which it mediates uterine vascular changes during gestation.